NODDI and Tensor-Based Microstructural Indices as Predictors of Functional Connectivity

In Diffusion Weighted MR Imaging (DWI), the signal is affected by the biophysical properties of neuronal cells and their relative placement, as well as extra-cellular tissue compartments. Typically, microstructural indices, such as fractional anisotropy (FA) and mean diffusivity (MD), are based on a tensor model that cannot disentangle the influence of these parameters. Recently, Neurite Orientation Dispersion and Density Imaging (NODDI) has exploited multi-shell acquisition protocols to model the diffusion signal as the contribution of three tissue compartments. NODDI microstructural indices, such as intra-cellular volume fraction (ICVF) and orientation dispersion index (ODI) are directly related to neuronal density and orientation dispersion, respectively. One way of examining the neurophysiological role of these microstructural indices across neuronal fibres is to look into how they relate to brain function. Here we exploit a statistical framework based on sparse Canonical Correlation Analysis (sCCA) and randomised Lasso to identify structural connections that are highly correlated with resting-state functional connectivity measured with simultaneous EEG-fMRI. Our results reveal distinct structural fingerprints for each microstructural index that also reflect their inter-relationships

Bundle-specific Tractogram Distribution Estimation Using Higher-order Streamline Differential Equation

Tractography traces the peak directions extracted from fiber orientation distribution (FOD) suffering from ambiguous spatial correspondences between diffusion directions and fiber geometry, which is prone to producing erroneous tracks while missing true positive connections. The peaks-based tractography methods 'locally' reconstructed streamlines in 'single to single' manner, thus lacking of global information about the trend of the whole fiber bundle. In this work, we propose a novel tractography method based on a bundle-specific tractogram distribution function by using a higher-order streamline differential equation, which reconstructs the streamline bundles in 'cluster to cluster' manner. A unified framework for any higher-order streamline differential equation is presented to describe the fiber bundles with disjoint streamlines defined based on the diffusion tensor vector field. At the global level, the tractography process is simplified as the estimation of bundle-specific tractogram distribution (BTD) coefficients by minimizing the energy optimization model, and is used to characterize the relations between BTD and diffusion tensor vector under the prior guidance by introducing the tractogram bundle information to provide anatomic priors. Experiments are performed on simulated Hough, Sine, Circle data, ISMRM 2015 Tractography Challenge data, FiberCup data, and in vivo data from the Human Connectome Project (HCP) data for qualitative and quantitative evaluation. The results demonstrate that our approach can reconstruct the complex global fiber bundles directly. BTD reduces the error deviation and accumulation at the local level and shows better results in reconstructing long-range, twisting, and large fanning tracts

Evaluating the accuracy of diffusion MRI models in white matter

Models of diffusion MRI within a voxel are useful for making inferences about the properties of the tissue and inferring fiber orientation distribution used by tractography algorithms. A useful model must fit the data accurately. However, evaluations of model-accuracy of some of the models that are commonly used in analyzing human white matter have not been published before. Here, we evaluate model-accuracy of the two main classes of diffusion MRI models. The diffusion tensor model (DTM) summarizes diffusion as a 3-dimensional Gaussian distribution. Sparse fascicle models (SFM) summarize the signal as a linear sum of signals originating from a collection of fascicles oriented in different directions. We use cross-validation to assess model-accuracy at different gradient amplitudes (b-values) throughout the white matter. Specifically, we fit each model to all the white matter voxels in one data set and then use the model to predict a second, independent data set. This is the first evaluation of model-accuracy of these models. In most of the white matter the DTM predicts the data more accurately than test-retest reliability; SFM model-accuracy is higher than test-retest reliability and also higher than the DTM, particularly for measurements with (a) a b-value above 1000 in locations containing fiber crossings, and (b) in the regions of the brain surrounding the optic radiations. The SFM also has better parameter-validity: it more accurately estimates the fiber orientation distribution function (fODF) in each voxel, which is useful for fiber tracking

Comparison of Brain Networks based on Predictive Models of Connectivity

In this study we adopt predictive modelling to identify simultaneously commonalities and differences in multi-modal brain networks acquired within subjects. Typically, predictive modelling of functional connectomes from structural connectomes explores commonalities across multimodal imaging data. However, direct application of multivariate approaches such as sparse Canonical Correlation Analysis (sCCA) applies on the vectorised elements of functional connectivity across subjects and it does not guarantee that the predicted models of functional connectivity are Symmetric Positive Matrices (SPD). We suggest an elegant solution based on the transportation of the connectivity matrices on a Riemannian manifold, which notably improves the prediction performance of the model. Randomised lasso is used to alleviate the dependency of the sCCA on the lasso parameters and control the false positive rate. Subsequently, the binomial distribution is exploited to set a threshold statistic that reflects whether a connection is selected or rejected by chance. Finally, we estimate the sCCA loadings based on a de-noising approach that improves the estimation of the coefficients. We validate our approach based on resting-state fMRI and diffusion weighted MRI data. Quantitative validation of the prediction performance shows superior performance, whereas qualitative results of the identification process are promising.Comment: 7 pages, 4 figure

MULTIVARIATE MODELING OF COGNITIVE PERFORMANCE AND CATEGORICAL PERCEPTION FROM NEUROIMAGING DATA

State-of-the-art cognitive-neuroscience mainly uses hypothesis-driven statistical testing to characterize and model neural disorders and diseases. While such techniques have proven to be powerful in understanding diseases and disorders, they are inadequate in explaining causal relationships as well as individuality and variations. In this study, we proposed multivariate data-driven approaches for predictive modeling of cognitive events and disorders. We developed network descriptions of both structural and functional connectivities that are critical in multivariate modeling of cognitive performance (i.e., fluency, attention, and working memory) and categorical perceptions (i.e., emotion, speech perception). We also performed dynamic network analysis on brain connectivity measures to determine the role of different functional areas in relation to categorical perceptions and cognitive events. Our empirical studies of structural connectivity were performed using Diffusion Tensor Imaging (DTI). The main objective was to discover the role of structural connectivity in selecting clinically interpretable features that are consistent over a large range of model parameters in classifying cognitive performances in relation to Acute Lymphoblastic Leukemia (ALL). The proposed approach substantially improved accuracy (13% - 26%) over existing models and also selected a relevant, small subset of features that were verified by domain experts. In summary, the proposed approach produced interpretable models with better generalization.Functional connectivity is related to similar patterns of activation in different brain regions regardless of the apparent physical connectedness of the regions. The proposed data-driven approach to the source localized electroencephalogram (EEG) data includes an array of tools such as graph mining, feature selection, and multivariate analysis to determine the functional connectivity in categorical perceptions. We used the network description to correctly classify listeners behavioral responses with an accuracy over 92% on 35 participants. State-of-the-art network description of human brain assumes static connectivities. However, brain networks in relation to perception and cognition are complex and dynamic. Analysis of transient functional networks with spatiotemporal variations to understand cognitive functions remains challenging. One of the critical missing links is the lack of sophisticated methodologies in understanding dynamics neural activity patterns. We proposed a clustering-based complex dynamic network analysis on source localized EEG data to understand the commonality and differences in gender-specific emotion processing. Besides, we also adopted Bayesian nonparametric framework for segmentation neural activity with a finite number of microstates. This approach enabled us to find the default network and transient pattern of the underlying neural mechanism in relation to categorical perception. In summary, multivariate and dynamic network analysis methods developed in this dissertation to analyze structural and functional connectivities will have a far-reaching impact on computational neuroscience to identify meaningful changes in spatiotemporal brain activities

Characterising the neurobiological mechanisms of action of exercise and cognitive behavioural interventions for rheumatoid arthritis fatigue: an MRI brain study

Objective: Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive–behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. Methods: A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). Results: Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ßAverage = −0.46, SD 0.61; ßAverage = −0.32, SD 0.47, respectively). Conclusion: The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting

Statistical Diffusion Tensor Imaging

Magnetic resonance diffusion tensor imaging (DTI) allows to infere the ultrastructure of living tissue. In brain mapping, neural fiber trajectories can be identified by exploiting the anisotropy of diffusion processes. Manifold statistical methods may be linked into the comprehensive processing chain that is spanned between DTI raw images and the reliable visualization of fibers. In this work, a space varying coefficients model (SVCM) using penalized B-splines was developed to integrate diffusion tensor estimation, regularization and interpolation into a unified framework. The implementation challenges originating in multiple 3d space varying coefficient surfaces and the large dimensions of realistic datasets were met by incorporating matrix sparsity and efficient model approximation. Superiority of B-spline based SVCM to the standard approach was demonstrable from simulation studies in terms of the precision and accuracy of the individual tensor elements. The integration with a probabilistic fiber tractography algorithm and application on real brain data revealed that the unified approach is at least equivalent to the serial application of voxelwise estimation, smoothing and interpolation. From the error analysis using boxplots and visual inspection the conclusion was drawn that both the standard approach and the B-spline based SVCM may suffer from low local adaptivity. Therefore, wavelet basis functions were employed for filtering diffusion tensor fields. While excellent local smoothing was indeed achieved by combining voxelwise tensor estimation with wavelet filtering, no immediate improvement was gained for fiber tracking. However, the thresholding strategy needs to be refined and the proposed model of an incorporation of wavelets into an SVCM needs to be implemented to finally assess their utility for DTI data processing. In summary, an SVCM with specific consideration of the demands of human brain DTI data was developed and implemented, eventually representing a unified postprocessing framework. This represents an experimental and statistical platform to further improve the reliability of tractography

Neurobiological markers for remission and persistence of childhood attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in children. Symptoms of childhood ADHD persist into adulthood in around 65% of patients, which elevates the risk for a number of adverse outcomes, resulting in substantial individual and societal burden. A neurodevelopmental double dissociation model is proposed based on existing studies in which the early onset of childhood ADHD is suggested to associate with dysfunctional subcortical structures that remain static throughout the lifetime; while diminution of symptoms over development could link to optimal development of prefrontal cortex. Current existing studies only assess basic measures including regional brain activation and connectivity, which have limited capacity to characterize the functional brain as a high performance parallel information processing system, the field lacks systems-level investigations of the structural and functional patterns that significantly contribute to the symptom remission and persistence in adults with childhood ADHD. Furthermore, traditional statistical methods estimate group differences only within a voxel or region of interest (ROI) at a time without having the capacity to explore how ROIs interact in linear and/or non-linear ways, as they quickly become overburdened when attempting to combine predictors and their interactions from high-dimensional imaging data set. This dissertation is the first study to apply ensemble learning techniques (ELT) in multimodal neuroimaging features from a sample of adults with childhood ADHD and controls, who have been clinically followed up since childhood. A total of 36 adult probands who were diagnosed with ADHD combined-type during childhood and 36 matched normal controls (NCs) are involved in this dissertation research. Thirty-six adult probands are further split into 18 remitters (ADHD-R) and 18 persisters (ADHD-P) based on the symptoms in their adulthood from DSM-IV ADHD criteria. Cued attention task-based fMRI, structural MRI, and diffusion tensor imaging data from each individual are analyzed. The high-dimensional neuroimaging features, including pair-wise regional connectivity and global/nodal topological properties of the functional brain network for cue-evoked attention process, regional cortical thickness and surface area, subcortical volume, volume and fractional anisotropy of major white matter fiber tract for each subject are calculated. In addition, all the currently available optimization strategies for ensemble learning techniques (i.e., voting, bagging, boosting and stacking techniques) are tested in a pool of semi-final classification results generated by seven basic classifiers, including K-Nearest Neighbors, support vector machine (SVM), logistic regression, Naïve Bayes, linear discriminant analysis, random forest, and multilayer perceptron. As hypothesized, results indicate that the features of nodal efficiency in right inferior frontal gyrus, right middle frontal (MFG)-inferior parietal (IPL) functional connectivity, and right amygdala volume significantly contributed to accurate discrimination between ADHD probands and controls; higher nodal efficiency of right MFG greatly contributed to inattentive and hyperactive/impulsive symptom remission, while higher right MFG-IPL functional connectivity strongly linked to symptom persistence in adults with childhood ADHD. The utilization of ELTs indicates that the bagging-based ELT with the base model of SVM achieves the best results, with the most significant improvement of the area under the receiver of operating characteristic curve (0.89 for ADHD probands vs. NCs, and 0.9 for ADHD-P vs. ADHD-R). The outcomes of this dissertation research have considerable value for the development of novel interventions that target mechanisms associated with recovery

The Impact of Temporal Lobe Epilepsy Surgery on Picture Naming and its Relationship to Network Metric Change

Background: Anterior temporal lobe resection (ATLR) is a successful treatment for medically-refractory temporal lobe epilepsy (TLE). In the language-dominant hemisphere, 30%- 50% of individuals experience a naming decline which can impact upon daily life. Measures of structural networks are associated with language performance pre-operatively. It is unclear if analysis of network measures may predict post-operative decline. Methods: White matter fibre tractography was performed on preoperative diffusion MRI of 44 left lateralised and left resection individuals with TLE to reconstruct the preoperative structural network. Resection masks, drawn on co-registered pre- and post-operative T1-weighted MRI scans, were used as exclusion regions on pre-operative tractography to estimate the post-operative network. Changes in graph theory metrics, cortical strength, betweenness centrality, and clustering coefficient were generated by comparing the estimated pre- and post-operative networks. These were thresholded based on the presence of the connection in each patient, ranging from 75% to 100% in steps of 5%. The average graph theory metric across thresholds was taken. We incorporated leave-one-out cross-validation with smoothly clipped absolute deviation (SCAD) least absolute shrinkage and selection operator (LASSO) feature selection and a support vector classifier to assess graph theory metrics on picture naming decline. Picture naming was assessed via the Graded Naming Test preoperatively and at 3 and 12 months post-operatively and the outcome was classified using the reliable change index (RCI) to identify clinically significant decline. The best feature combination and model was selected using the area under the curve (AUC). The sensitivity, specificity and F1-score were also reported. Permutation testing was performed to assess the machine learning model and selected regions difference significance. Results: A combination of clinical and graph theory metrics were able to classify outcome of picture naming at 3 months with an AUC of 0.84. At 12 months, change in strength to cortical regions was best able to correctly classify outcome with an AUC of 0.86. Longitudinal analysis revealed that betweenness centrality was the best metric to identify patients who declined at 3 months, who will then continue to experience decline from 3-12 months. Both models were significantly higher AUC values than a random classifier. Conclusion: Our results suggest that inferred changes of network integrity were able to correctly classify picture naming decline after ATLR. These measures may be used to prospectively to identify patients who are at risk of picture naming decline after surgery and could potentially be utilised to assist tailoring the resection in order to prevent this decline

Flexibly adapting to emotional cues: Examining the functional and structural correlates of emotional reactivity and emotion control in healthy and depressed individuals

The ability of emotionally significant stimuli to bias our behaviour is an evolutionarily adaptive phenomenon. However, sometimes emotions become excessive, inappropriate, and even pathological, like in major depressive disorder (MDD). Emotional flexibility includes both the neural processes involved in reacting to, or representing, emotional significance, and those involved in controlling emotional reactivity. MDD represents a potentially distinct form of emotion (in)flexibility, and therefore offers a unique perspective for understanding both the integration of conflicting emotional cues and the neural regions involved in actively controlling emotional systems. The present investigation of emotional flexibility began by considering the functional neural correlates of competing socio-emotional cues and effortful emotion regulation in MDD using both negative and positive emotions. Study 1 revealed greater amygdala activity in MDD relative to control participants when negative cues were centrally presented and task-relevant. No significant between-group differences were observed in the amygdala for peripheral task-irrelevant negative distracters. However, controls demonstrated greater recruitment of the ventrolateral (vlPFC) and dorsomedial prefrontal cortices (dmPFC) implicated in emotion control. Conversely, attenuated amygdala activity for task-relevant and irrelevant positive cues was observed in depressed participants. In Study 2, effortful emotion regulation using strategies adapted from cognitive behaviour therapy (CBT) revealed greater activity in regions of the dorsal and lateral prefrontal cortices in both MDD and control participants when attempting to either down-regulate negative or up-regulate positive emotions. During the down-regulation of negative cues, only controls displayed a significant reduction of amygdala activity. In Study 3, an individual differences approach using multiple regression revealed that while greater amygdala-vmPFC structural connectivity was associated with low trait-anxiety, greater connectivity between amygdala and regions of occipitotemporal and parietal cortices was associated with high trait-anxiety. These findings are discussed with respect to current models of emotional reactivity and emotion control derived from studies of both healthy individuals and those with emotional disorders, particularly depression. The focus is on amygdala variability in differing contexts, the role of the vmPFC in the modulation of amygdala activity via learning processes, and the modulation of emotion by attention or cognitive control mechanisms initiated by regions of frontoparietal cortices